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New approach for two chromene carboxylic acids having a fully substituted benzene ring
Tetrahedron Letters Tetrahedron Letters 45 (2004) 6971–6973
New approach for two chromene carboxylic acids having a fully substituted benzene ring Seiji Yamaguchi,* Mikiko Maekawa, Yohei Murayama, Masahiro Miyazawa and Yoshiro Hirai Department of Chemistry, Faculty of Science, Toyama University, Toyama 930-8555, Japan Received 11 June 2004; revised 5 July 2004; accepted 8 July 2004 Available online 10 August 2004
Abstract—Two chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2), were synthesized via thermal cyclization of the corresponding four substituted phenyl propargyl ethers. Ó 2004 Elsevier Ltd. All rights reserved.
Many 2H-chromenes, having a long side-chain at position 2, have been isolated from various plants.1 In our previous paper, we reported a new approach for natural cannabichromene using condensation of a salicyl aldehyde with isopropylidenemalonate giving 2H-chromene-2-acetate and following side-chain conversion.2 We also reported another approach for teretifolione B using regioselective thermal cyclization of the corresponding phenyl propargyl ether.3 Now, in this paper, the syntheses of two 2H-chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1), isolated from Cylindrocapron olidum,4 and mycochromenic acid (2), isolated from Penicillium brevicompactum,5 are described (Scheme 1). OR
OH OHC
HO2C H3C
H 3C
O
O Cl
Cl
8-chlorocannabiorcichromenic acid (1)
(3) OMe
OMe H3 C
H3C O O
Once, respective approaches to natural 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2) used the condensation method, but the results were unsuccessful.6 For respective approaches of natural 1 and 2 using the thermal cyclization method, both efficient preparation of the corresponding propargyl ethers 3 and 4 and effective cyclization might be needed. Some papers described that some propargyl ethers having an electron-withdrawing carbonyl group showed low yields in cyclization, but we showed these were ambiguous, in our previous paper.3 In the paper, we also described the regioselectivity in thermal cyclization. These two chromene carboxylic acids show a fully substituted benzene ring. And we might expect more effective cyclization of 3 and 4, because they have the only site for cyclization.
O
CO2H
O
mycochromenic acid (2)
O
OMOM
O
(4)
Scheme 1. Strategy for 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2) via thermal cyclization. * Corresponding author. Tel.: +81-76-445-6617; fax: +81-76-4456549; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.07.059
The substrate 3 might be prepared by coupling of 3-chloro-4-hydroxy-2-methyl-6-(protected)oxybenzaldehyde 5 with 3,7-dimethyl-oct-6-en-1-yn-3-yl methyl carbonate 6b and the substrate 4 might be prepared by coupling of 7-hydroxy-4-methyl-5-(protected)oxyphthalide 9 with 3-methyl-6-(protected)oxy-oct-1-yn-3-yl methyl carbonate 6c. As the starting material for 1, 3-chloro-4,6-dihydroxy-2methylbenzaldehyde 5c, was prepared from 3,5-dimethoxytoluene in three steps: (1) Vilsmeier formylation with DMF–POCl3 (90%), (2) chlorination with NCS–DMF (75%), (3) deprotection with BBr3 (95%), and then converted to its 6-methoxy derivative 5a in three steps: (1) MOM protection with MOMCl–diisopropylamine (99%), (2) methylation with Me2SO4–K2CO3 (92%), (3)
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S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
deprotection with MeOH–concd. HCl (57%) and to its 6-MOMoxy derivative 5b in three steps: (1) acetylation with Ac2O–pyridine (81%), (2) MOM protection with MOMCl–diisopropylamine (99%), (3) deprotection with aq NaOH–EtOH (63%) (Scheme 2). As the stating material for 2, 7-hydroxy-5-methoxy-4methylphthalide 9, was prepared from 3,5-dimethoxybenyl methyl ether in six steps: (1) Vilsmeier formylation with DMF–POCl3 (93%), (2) Wolf-Kishner reduction with NH2NH2–KOH (89%), (3) Vilsmeier formylation with DMF–POCl3 (75%), (4) oxidation with NaClO2 (61%), (5) lactonization with NaOH (64%), (6) selective demethylation with MgI2–OEt2 (72%). Coupling and thermal cyclization of 5a were prestudied with a dimethyl analog; coupling of 5a with methyl 2methylbut-3-yn-2-yl carbonate 6a using CuCl2–DBU gave the corresponding propargyl ether 3aa (77%), and the following thermal cyclization gave 2,2-dimethyl2H-chromene 7aa (68%). And, 7aa was converted to 5hydroxy-6-carboxylic acid 8ca by demethylation with MgI2–OEt2 (50%) followed by oxidation with NaClO2 (41%).
OR OHC
MeO2CO
R1
OH (6a; R1 = H) (6b; R1 = prenyl) (5a; R = Me) (5b; R = MOM) (5c; R = H) Me
Similar coupling of 5a with 3,7-dimethyl-oct-6-en-1-yn3-yl methyl carbonate 6b gave propargyl ether 3ab (76%), and the following thermal cyclization gave the corresponding 2H-chromene 7ab (82%). Demethylation of 7ab with MgI2–OEt2 gave 5-hydroxy-6-carbaldehyde 7cb (45%), and oxidation of 7ab gave 5-methoxy-6-carboxylic acid 8ab (71%). But, for both conversions to 1, oxidation of 7cb and demethylation of 8ab (50%) were unsuccessful. So, MOMprotected 5b was prepared and subjected to a similar conversion. Similar coupling of 5b with 3,7-dimethyl-oct-6-en-1-yn3-yl methyl carbonate 6b gave propargyl ether 3bb (56%), and the following thermal cyclization gave the corresponding 2H-chromene 7bb (62%). And, 7bb was converted to 5-hydroxy-6-carboxylic acid 1 by oxidation with NaClO2 followed by deprotection (43% in two steps) (Scheme 3). Coupling and thermal cyclization of 7-hydroxyphthalide 9 were also prestudied with a dimethyl analog; coupling of 9 with methyl 2-methylbut-3-yn-2-yl carbonate 6a using CuCl2–DBU gave the correspond-
160oC
OR OHC
OR OHC
N,N-dimethylaniline
Me
R1
O
(thermal cyclization)
Me
R1
O Cl
Cl
Cl
(7aa; R = Me, R1 = H) 68% from 3aa (7ab; R = Me, R1 = prenyl) 82% from 3ab (7bb; R = MOM, R1 = prenyl) 62% from 3bb (7ca; R = H, R1 = H) 50% from 7aa (7cb; R = H, R1 = prenyl) 45% from 7ab
(3aa; R = Me, R1 = H) 77% (3ab; R = Me, R1 = prenyl) 76% (3bb; R = MOM, R1 = prenyl) 56%
NaClO2
(oxidation)
OR HO2C R1 O Cl (8ca; R = H, R1 = H) 41% from 7ca (8ab; R = Me, R1 = prenyl) 71% from 7ab (8ba; R = MOM, R1 = prenyl) (1; R = H, R1 = prenyl) 43% in two steps from 7bb Me
Scheme 2. Approach for 8-chlorocannabiorcichromenic acid (1) via thermal cyclization.
OMe Me O
O 9
MeO2CO
R
160oC
OMe
OH 6a (R1 = H) 6c (R1 = CH2CH2CH2OMOM)
O O
OMe
N,N-dimethylaniline
Me R
(thermal cyclization)
O
(4a; R = H) 63% (4c; R = CH2CH2CH2OMOM) 66%
Scheme 3. Approach for mycochromenic acid (2) via thermal cyclization.
Me O O
R
O
(10a; R = H) 64% from 4a (10c; R = CH2CH2CH2OMOM) 89% from 4c (10d; R = CH2CH2CH2OH) 99% from 10c (10c; R = CH2CH2CHO) 30% from 10d (2; R = CH2CH2CO2H) 89% in two steps from 10d
S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
ing propargyl ether 4a (63%), and the following thermal cyclization gave 2,2-dimethyl-2H-chromene 10a (64%).
mycochromenic data.4,5
acid
6973
in
all
reported
spectral
References and notes Similar coupling of 9 with 6-MOMoxy-3-methylhex-1yn-3-yl methyl carbonate 6c gave propargyl ether 4c (66%), and the following thermal cyclization gave the corresponding 2H-chromene 10c (89%). And, 10c was converted to mycochromenic acid 2 (49%) in three steps: (1) deprotection with MeOH–concd. HCl giving 10d, (2) oxidation with PDC giving 10e, (3) oxidation with Ag2O giving mycochromenic acid 2. Both chromene carboxylic acid 1 and 2 were identical with natural 8-chlorocannabiorcichromenic acid and
1. Ellis, G. P. Chromenes, Chromanones and Chromones; John Wiley & Sons: New York, 1977; p 31. 2. Yamaguchi, S.; Shouji, N.; Kuroda, K. Bull. Chem. Soc. Jpn. 1995, 68, 305. 3. Yamaguchi, S.; Ishibashi, M.; Akasaka, K.; Yokoyama, H.; Miyazawa, M.; Hirai, Y. Tetrahedron Lett. 2001, 42, 1091. 4. Quaghebeur, K.; Coosemans, J.; Toppet, S.; Compernolle, F. Phytochemistry 1994, 37, 159. 5. Campbel, I. M.; Calzadilla, C. H.; McCorkindale, N. J. Tetrahedron Lett. 1966, 42, 51. 6. These details will be reported soon in a full paper.
New approach for two chromene carboxylic acids having a fully substituted benzene ring Seiji Yamaguchi,* Mikiko Maekawa, Yohei Murayama, Masahiro Miyazawa and Yoshiro Hirai Department of Chemistry, Faculty of Science, Toyama University, Toyama 930-8555, Japan Received 11 June 2004; revised 5 July 2004; accepted 8 July 2004 Available online 10 August 2004
Abstract—Two chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2), were synthesized via thermal cyclization of the corresponding four substituted phenyl propargyl ethers. Ó 2004 Elsevier Ltd. All rights reserved.
Many 2H-chromenes, having a long side-chain at position 2, have been isolated from various plants.1 In our previous paper, we reported a new approach for natural cannabichromene using condensation of a salicyl aldehyde with isopropylidenemalonate giving 2H-chromene-2-acetate and following side-chain conversion.2 We also reported another approach for teretifolione B using regioselective thermal cyclization of the corresponding phenyl propargyl ether.3 Now, in this paper, the syntheses of two 2H-chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1), isolated from Cylindrocapron olidum,4 and mycochromenic acid (2), isolated from Penicillium brevicompactum,5 are described (Scheme 1). OR
OH OHC
HO2C H3C
H 3C
O
O Cl
Cl
8-chlorocannabiorcichromenic acid (1)
(3) OMe
OMe H3 C
H3C O O
Once, respective approaches to natural 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2) used the condensation method, but the results were unsuccessful.6 For respective approaches of natural 1 and 2 using the thermal cyclization method, both efficient preparation of the corresponding propargyl ethers 3 and 4 and effective cyclization might be needed. Some papers described that some propargyl ethers having an electron-withdrawing carbonyl group showed low yields in cyclization, but we showed these were ambiguous, in our previous paper.3 In the paper, we also described the regioselectivity in thermal cyclization. These two chromene carboxylic acids show a fully substituted benzene ring. And we might expect more effective cyclization of 3 and 4, because they have the only site for cyclization.
O
CO2H
O
mycochromenic acid (2)
O
OMOM
O
(4)
Scheme 1. Strategy for 8-chlorocannabiorcichromenic acid (1) and mycochromenic acid (2) via thermal cyclization. * Corresponding author. Tel.: +81-76-445-6617; fax: +81-76-4456549; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.07.059
The substrate 3 might be prepared by coupling of 3-chloro-4-hydroxy-2-methyl-6-(protected)oxybenzaldehyde 5 with 3,7-dimethyl-oct-6-en-1-yn-3-yl methyl carbonate 6b and the substrate 4 might be prepared by coupling of 7-hydroxy-4-methyl-5-(protected)oxyphthalide 9 with 3-methyl-6-(protected)oxy-oct-1-yn-3-yl methyl carbonate 6c. As the starting material for 1, 3-chloro-4,6-dihydroxy-2methylbenzaldehyde 5c, was prepared from 3,5-dimethoxytoluene in three steps: (1) Vilsmeier formylation with DMF–POCl3 (90%), (2) chlorination with NCS–DMF (75%), (3) deprotection with BBr3 (95%), and then converted to its 6-methoxy derivative 5a in three steps: (1) MOM protection with MOMCl–diisopropylamine (99%), (2) methylation with Me2SO4–K2CO3 (92%), (3)
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S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
deprotection with MeOH–concd. HCl (57%) and to its 6-MOMoxy derivative 5b in three steps: (1) acetylation with Ac2O–pyridine (81%), (2) MOM protection with MOMCl–diisopropylamine (99%), (3) deprotection with aq NaOH–EtOH (63%) (Scheme 2). As the stating material for 2, 7-hydroxy-5-methoxy-4methylphthalide 9, was prepared from 3,5-dimethoxybenyl methyl ether in six steps: (1) Vilsmeier formylation with DMF–POCl3 (93%), (2) Wolf-Kishner reduction with NH2NH2–KOH (89%), (3) Vilsmeier formylation with DMF–POCl3 (75%), (4) oxidation with NaClO2 (61%), (5) lactonization with NaOH (64%), (6) selective demethylation with MgI2–OEt2 (72%). Coupling and thermal cyclization of 5a were prestudied with a dimethyl analog; coupling of 5a with methyl 2methylbut-3-yn-2-yl carbonate 6a using CuCl2–DBU gave the corresponding propargyl ether 3aa (77%), and the following thermal cyclization gave 2,2-dimethyl2H-chromene 7aa (68%). And, 7aa was converted to 5hydroxy-6-carboxylic acid 8ca by demethylation with MgI2–OEt2 (50%) followed by oxidation with NaClO2 (41%).
OR OHC
MeO2CO
R1
OH (6a; R1 = H) (6b; R1 = prenyl) (5a; R = Me) (5b; R = MOM) (5c; R = H) Me
Similar coupling of 5a with 3,7-dimethyl-oct-6-en-1-yn3-yl methyl carbonate 6b gave propargyl ether 3ab (76%), and the following thermal cyclization gave the corresponding 2H-chromene 7ab (82%). Demethylation of 7ab with MgI2–OEt2 gave 5-hydroxy-6-carbaldehyde 7cb (45%), and oxidation of 7ab gave 5-methoxy-6-carboxylic acid 8ab (71%). But, for both conversions to 1, oxidation of 7cb and demethylation of 8ab (50%) were unsuccessful. So, MOMprotected 5b was prepared and subjected to a similar conversion. Similar coupling of 5b with 3,7-dimethyl-oct-6-en-1-yn3-yl methyl carbonate 6b gave propargyl ether 3bb (56%), and the following thermal cyclization gave the corresponding 2H-chromene 7bb (62%). And, 7bb was converted to 5-hydroxy-6-carboxylic acid 1 by oxidation with NaClO2 followed by deprotection (43% in two steps) (Scheme 3). Coupling and thermal cyclization of 7-hydroxyphthalide 9 were also prestudied with a dimethyl analog; coupling of 9 with methyl 2-methylbut-3-yn-2-yl carbonate 6a using CuCl2–DBU gave the correspond-
160oC
OR OHC
OR OHC
N,N-dimethylaniline
Me
R1
O
(thermal cyclization)
Me
R1
O Cl
Cl
Cl
(7aa; R = Me, R1 = H) 68% from 3aa (7ab; R = Me, R1 = prenyl) 82% from 3ab (7bb; R = MOM, R1 = prenyl) 62% from 3bb (7ca; R = H, R1 = H) 50% from 7aa (7cb; R = H, R1 = prenyl) 45% from 7ab
(3aa; R = Me, R1 = H) 77% (3ab; R = Me, R1 = prenyl) 76% (3bb; R = MOM, R1 = prenyl) 56%
NaClO2
(oxidation)
OR HO2C R1 O Cl (8ca; R = H, R1 = H) 41% from 7ca (8ab; R = Me, R1 = prenyl) 71% from 7ab (8ba; R = MOM, R1 = prenyl) (1; R = H, R1 = prenyl) 43% in two steps from 7bb Me
Scheme 2. Approach for 8-chlorocannabiorcichromenic acid (1) via thermal cyclization.
OMe Me O
O 9
MeO2CO
R
160oC
OMe
OH 6a (R1 = H) 6c (R1 = CH2CH2CH2OMOM)
O O
OMe
N,N-dimethylaniline
Me R
(thermal cyclization)
O
(4a; R = H) 63% (4c; R = CH2CH2CH2OMOM) 66%
Scheme 3. Approach for mycochromenic acid (2) via thermal cyclization.
Me O O
R
O
(10a; R = H) 64% from 4a (10c; R = CH2CH2CH2OMOM) 89% from 4c (10d; R = CH2CH2CH2OH) 99% from 10c (10c; R = CH2CH2CHO) 30% from 10d (2; R = CH2CH2CO2H) 89% in two steps from 10d
S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
ing propargyl ether 4a (63%), and the following thermal cyclization gave 2,2-dimethyl-2H-chromene 10a (64%).
mycochromenic data.4,5
acid
6973
in
all
reported
spectral
References and notes Similar coupling of 9 with 6-MOMoxy-3-methylhex-1yn-3-yl methyl carbonate 6c gave propargyl ether 4c (66%), and the following thermal cyclization gave the corresponding 2H-chromene 10c (89%). And, 10c was converted to mycochromenic acid 2 (49%) in three steps: (1) deprotection with MeOH–concd. HCl giving 10d, (2) oxidation with PDC giving 10e, (3) oxidation with Ag2O giving mycochromenic acid 2. Both chromene carboxylic acid 1 and 2 were identical with natural 8-chlorocannabiorcichromenic acid and
1. Ellis, G. P. Chromenes, Chromanones and Chromones; John Wiley & Sons: New York, 1977; p 31. 2. Yamaguchi, S.; Shouji, N.; Kuroda, K. Bull. Chem. Soc. Jpn. 1995, 68, 305. 3. Yamaguchi, S.; Ishibashi, M.; Akasaka, K.; Yokoyama, H.; Miyazawa, M.; Hirai, Y. Tetrahedron Lett. 2001, 42, 1091. 4. Quaghebeur, K.; Coosemans, J.; Toppet, S.; Compernolle, F. Phytochemistry 1994, 37, 159. 5. Campbel, I. M.; Calzadilla, C. H.; McCorkindale, N. J. Tetrahedron Lett. 1966, 42, 51. 6. These details will be reported soon in a full paper.